The invention generally relates to methods for treating infections.
A microbial infection such as, for example, Pneumocystis carinii pneumonia (PCP), is believed to be one of the leading causes of death in patients suffering from AIDS. Pentamidine [i.e., 1,5-bis(4-amidinophenoxy)pentane] has been used as a therapeutic agent for the treatment of PCP by intravenous infusion and as a prophylactic agent by aerosol dosage. However, the use of this drug may be potentially disadvantageous in that it might be toxic and contribute to hypotension, hypoglycemia, and cardiac arrhythmias experienced by the patient taking pentamidine.
Recent efforts have focused on developing other compounds for potentially treating PCP. A number of aromatic diamidines have displayed potential anti-PCP activity as reported in Boykin D. W., et al., J. Med. Chem., 1995, pp. 912-916; Tidwell, R. R. et al., Antimicrob. Agents Chemother. 1993, 37, p. 1713; Lombardy, R. L. et al., J. Med. Chem. 1996, 39, p. 1452; and Kumar, A. et al., J. Med. Chem., 1996, 31, p. 767. Notwithstanding any advantages that these drugs may possess, they may be potentially undesirable since the drugs often exhibit low oral bioavailability.
Chemical modification of drugs into prodrugs can potentially improve physiochemical properties such as water solubility, lipophilicity, transport of drug to the site of action, and presystemic degradation, thus improving oral bioavailability. See Bundgaard, H., In Design of Prodrugs; Bundgaard, H.;Ed.; Elsevier: Amsterdam, The Netherlands, 1985; pp. 1-92; and Bundgaard, H., In A Textbook of Drug Design and Development, Krogsgaard-Larsen, P.; Bundgaard, H.; Ed.; Harwood Academic Publ. Switzerland, 1991, pp. 113-191. A number of reports exist on the prodrug modification of carboxyl, hydroxyl, thiols, and amino compounds. See, for example, Friis, G. J., et al., In A Textbook of Drug Design and Development, 2nd Ed., Krogsgaard-Larsen, P., Liljefors, T. Madsen, U.; Ed.; Overseas Pub: Amsterdam, The Netherlands, 1996, pp. 351-385; Digenis, G. A., et al., Drug latentiation, Handbook of Experimental Pharmacology, 1975, 28, pp. 86-112. Moreover, Weller et al. (J. Med. Chem., 1996, 39, pp. 3139-3146) propose employing amidoximes and carbamate derivatives of mono-amidines as prodrugs in order to potentially provide improved oral availability for fibrogen antagonists. In addition, Boykin, D. W., et al., (Bioorg. Med. Chem. Lett., 1996, 6, pp. 3017-3020) have reported that bis-amidoxime and O-methylamidoxime may be effective anti-PCP agents on both oral and intravenous administration. U.S. Pat. No. 5,723,495 to Hall et al. proposes administering a bis-benzamidoxime to a patient for treating Pneumocystis carinii. 
Notwithstanding the above efforts, there remains a need in the art to provide drugs that display improved activity.
A method of combating an infection to a subject in need of such a treatment is disclosed. The method comprises administering to the subject a compound of the formula (I): 
wherein:
X may be O, S, or NRxe2x80x2 wherein Rxe2x80x2 is H or loweralkyl;
R1 and R2 may be independently selected from the group consisting of H, loweralkyl, oxyalkyl, alkoxyalkyl, cycloalkyl, aryl, hydroxyalkyl, aminoalkyl, and alkylaminoalkyl;
R3 and R4 are each independently selected from the group consisting of H, loweralkyl, halogen, oxyalkyl, oxyaryl, and oxyarylalkyl;
R5 is represented by a formula selected from the group consisting of: 
xe2x80x83wherein:
X1, X2, and X3 are independently selected from O and S; and
R6 and R7 are independently selected from the group consisting of loweralkyl, aryl, alkylaryl, oxyaryl, an ester-containing substituent, and oxyalkyl;
or a pharmaceutically acceptable salt thereof, and wherein said compound of Formula (I) is administered in an amount to treat the infection.
Preferably, R6 and R7 are independently selected from the group consisting of:
CH3, CH2CCl3, CH2CH3, 
In one preferred embodiment, each of the substituents present on the compound of formula (I) represented by the formula: 
are present on the para positions of the aromatic groups on formula (I), although these substituents may be present in the meta positions.
The invention also discloses pharmaceutical compounds represented by the formula (I) described herein and pharmaceutically acceptable salts thereof, as well as pharmaceutical formulations comprising the pharmaceutical compounds of formula (I) and pharmaceutically acceptable carriers.